Using functional neuroimaging to determine local neuronal activity, we have found that normal subjects performing tasks involving working memory (WM) use a cortical network including dorsolateral prefrontal cortex, inferior parietal lobule, and inferior temporo-occipital cortex. In other tasks related to prefrontal cortex, we have shown, with word generation (verbal fluency) tasks that semantic and phonologic cues activate similar brain regions including anterior cingulate, left frontal cortex, thalamus and cerebellum, but subtle differences exist between them that are consistent with the lesion literature. Investigation of neural mechanisms involving verbal working memory has revealed bidirectional contributions of auditory-verbal WM in which retrieval of a perceptually based code relies on a ventral stream and sustained rehearsal processes depends on a dorsal pathway with a temporal lobe gateway to the motor system. In a study of cognitive activation in normal aging we found that neurophysiological changes were context dependent. That is, apparent changes over the life span differed in different tasks, depending on the role of the particular neural system for the particular task. In regions where physiological activity is normally suppressed when young subjects perform the tasks older subjects activate more, and, moreover, the more they activate (or fail to suppress), the worse they perform on the tasks. In other areas, where physiological activity is normally increased in young people performing the tasks, older subjects activate less; and the less they activate these regions, the more impaired their performance. Most recently, in a study which examined age-related reduction in WM capacity, our data revealed that the elderly reach their capacity of limitation sooner as compared with younger subjects. This demonstrates an inability of the elderly to keep the prefrontal cortex engaged at higher WM loads and the need to recruit more units of resources to maintain performance. We have also confirmed that large-scale changes in brain activity at the systems level (accompanying nonlinear changes in behavior) follow predictions from nonlinear dynamical theory, and we have defined discriminable frontal lobe regions (lateral prefrontal cortex and anterior cingulate cortex) that subserve different cognitive components in switching between tasks (overcoming the residual inhibition of previous task demands and initiating a new task, respectively). We have also shown that the neural system patterns activated in individual healthy subjects reflect their levels of performance and cognitive strategies (verbal versus spatial) on a working memory task and that frontal lobe functions during cognitive control can be dissected with functional imaging and task-switching paradigms. Building upon these findings, we have used neuroimaging to explore the effects in the brain of the catechol ? O-methyltransferase gene (COMT), which has been identified as a susceptibility gene for schizophrenia. It is well known that, particularly in prefrontal cortex, COMT is primarily involved in dopamine catabolism which influences cortical dopamine levels (as evidenced by the increase in dopamine in COMT knock-out mice). A common polymorphism in the COMT gene (val108/158met) leads to a significant reduction in methionine-coding allele enzyme activity in the prefrontal cortex (PFC). Postmortem studies have shown a direct correlation between valine-encoding alleles and increases in dopamine synthesis in the midbrain, which suggested that this functional single nucleotide polymorphism (SNP) can modulate the interaction between the PFC and the midbrain. Previous work has shown a relationship between activation of PFC neurons and dopaminergic receptors as they relate to working memory processes. The implication is that the COMT genotype aeffects the interaction of prefrontal activity and midbrain dopaminergic function. Based upon these findings, our group engaged in a study to demonstrate the specific interactions between PFC and midbrain dopamine synthesis in normal healthy living people as a function of COMT genotype. In the same individuals we measured both regional cerebral blood flow (rCBF) during working memory and [F-18] Fluoro-dopa uptake (to measure dopamine synthesis and presynaptic stores). Previous studies have described dopamine as being critical to determine the ratio of task-related to task-unrelated neural firing or ?tuning? of PFC neurons. Our findings that valine carriers have increased midbrain FDOPA uptake and that the COMT genotype determines the direction of the relationship between midbrain FDOPA and prefrontal rCBF during working memory substantiate the idea of strong interactions between PFC and dopamine and of genetic control of the PFC-midbrain tuning mechanism. These data provide for the first time important corroborative evidence in humans that supports current concepts about dopaminergic modulation of PFC function.